Ifetroban Treatment for Systemic Sclerosis

ABSTRACT

The present invention is directed to methods of treating, preventing, and/or ameliorating systemic sclerosis, by administration of a therapeutically effective amount of ifetroban or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The present invention is related to the use of thromboxane A₂ receptorantagonists (e.g., ifetroban) in the treatment and/or prevention ofsystemic sclerosis in mammals, e.g., humans, and pharmaceuticalcompositions for the same comprising thromboxane A₂ receptor antagonists(e.g., ifetroban) in an effective amount to treat and/or prevent thesediseases.

BACKGROUND OF THE INVENTION

Systemic sclerosis (SSc), also called scleroderma, is a rare autoimmuneconnective tissue disease. Systemic sclerosis is a complex andheterogeneous disease that is characterized by small vesselvasculopathy, autoantibody production, and excessive collagen depositionin the skin and internal organs (Karassa 2008). Systemic sclerosis isdivided into two broad categories: limited and diffuse cutaneous disease(dcSSc)(LeRoy 1988). Limited cutaneous disease (limited scleroderma orlcSSc) is characterized by thickening of the skin confined to the areadistal to the elbows and knees. The limited form of scleroderma tends tobe associated with less severe internal organ involvement or systemicinvolvement (Barnes 2012); however, such patients may develop SSc-PAH(systemic sclerosis—pulmonary arterial hypertension) with profoundeffects on morbidity and mortality. Organ fibrosis is generally limitedand slow to progress (Karassa 2008). Diffuse cutaneous disease (dcSSc)on the other hand involves skin thickening proximal to the elbows andknees and is associated with more rapid and severe internal organdamage. Diffuse cutaneous disease is characterized by rapidlyprogressing fibrosis and atrophy of the skin, joints and tendons,skeletal muscles, and internal organs including the lungs, heart,gastrointestinal tract, and kidney (Mayes 2008).

Usually the disease starts from the skin although visceral involvementmay occur prior to the cutaneous presentation, and in some cases (SScsine sclerosis) the skin may not appear to be involved. Polyarthralgiaand Raynaud's phenomenon are early and almost universal clinicalmanifestations (Karassa 2008) and may precede other features by monthsto years. Subcutaneous edema is common in the early stages buteventually the skin becomes thickened and hidebound, with loss of normalfolds. Telangiectasia, pigmentation, and depigmentation arecharacteristic signs. Digital ulceration and subcutaneous calcificationare also seen. Skin-thickness progression rate has been identified as amethod of predicting significant organ involvement including cardiacdisease (Parks 2014) and has been traditionally been considered as auseful marker both of current severity and future prognosis (Karassa2008). The clinical semi-quantitative assessment of skin thickness(modified Rodnan skin score [mRSS]) is currently the gold standard andthe main outcome measure used in clinical trials of SScdisease-modifying agents (Castro 2010).

Pulmonary disease has emerged as the major cause of death in sclerodermapatients (Black 2005). In SSc, the two most common types of directpulmonary involvement are interstitial lung disease (ILD) and pulmonaryhypertension (PH), which together account for 60% of all SSc relateddeaths. ILD is common in SSc. In early autopsy studies, up to 100% ofpatients were found to have parenchymal involvement. Parenchymal lunginvolvement appears early after the diagnosis of SSc, with 25% ofpatients developing clinically significant lung disease within 3 years.Patients with SSc can develop PH caused by pulmonary arterialhypertension (PAH), left ventricular disease or pulmonary fibrosis(Sweiss). PH can occur in all forms of SSc and is associated with earlymortality. The presence of PAH is variable (Solomon 2013) and is morecommon in patients with lcSSc (Sweiss). Pulmonary arterial hypertensionis initially silent, and early symptoms can be nonspecific. Dyspnea is alater symptom and can be attributed to multiple factors. Pulmonaryarterial hypertension in SSc typically develops late in the course ofpatients with lcSSC (Mayes 2008). Left untreated, between 45 to 60% ofthe patients with PAH of any cause will die within 2 years of diagnosis.When it occurs as a manifestation of scleroderma, PAH is particularlysevere and 1-year survival following diagnosis is approximately 55%(Black 2005), although survival seems to have improved since theintroduction of current PAH-specific therapies such as prostanoids,endothelin receptor antagonists and phosphodiesterase type 5 inhibitors.

At present, there are no specific diagnostic tests for SSc. However, itis well recognized that the presence of specific autoantibodies is oneof the most common manifestation of SSc and greater than 90% of SScpatients harbor antinuclear antibodies in their serum. Some of these arehighly specific for SSc, including anti-Scl-70 and anti-centromereantibodies. Anti-Scl-70 antibodies are directed against DNAtopoisomerase I and are almost exclusively present in the sera ofpatients with dcSSc. Anti-Scl-70 antibodies also correlate with thedevelopment of severe interstitial lung disease. Anti-centromereantibodies, on the other hand, are associated with the presence of lcSScand the propensity to develop PAH.

Cytokine, chemokine, and growth factor alterations have been found inhigher levels in both dcSSc and lcSSc. Numerous other cytokines,chemokines and regulatory proteins that are considered importantparticipants in the immune activation of SSc have been suggested aspotential biomarkers, including cluster of differentiation 40 (CD-40),chemokine ligand 2 (CCL-2), interleukin 15 (IL-15), interleukin 23(IL-23), B-cell activating factor (BAFF), FAS receptor (FasR), andothers. Elevated cytokines have been also been reported in SSc patientswith anti-Scl-70 auto-antibodies (Castro 2008).

Recently, endothelial-1 (ET-1), a potent vasoconstrictor, has been shownto be significantly elevated in SSc patients with PAH and withanti-centromere antibodies. Furthermore, there was a positivecorrelation between these levels and systolic pulmonary pressure.N-terminal probrain natriuretic peptide (NT-pro-BNP), although notspecific for PAH, reflects the myocardial response to various stimuli,such as mechanical stretch or hypoxia. ET-1 also plays a role invasculopathy and smooth muscle cell proliferation. ET-1 levels werefound to be elevated in SSs patients and to increase following exposureto cold and the triggering of the Raynaud's phenomenon. Elevated ET-1levels also correlated with other indicators of endothelial cellactivation, such as increased levels of von Willebrand factor, as wellas with the levels of other endothelial cell proteins, such asthrombomodulin and adhesion molecules, including soluble IntercellularAdhesion Molecule 1 (ICAM-1) and soluble Vascular Cell AdhesionMolecule-1 (VCAM-1). Elevated expression of ET-1 and ET receptors inpulmonary parenchyma are present at early stages of development ofinterstitial lung disease and fibrosing alveolitis of SSc. Increasedexpression of Endothelial Leukocyte Adhesion Molecule-1 (ELAM-1),ICAM-1, and VCAM-1 have been found in affected skin from SSc patientsand may participate in the early stages of tissue fibrosis (Castro2008).

Transforming growth factor beta (TGF-β) is known to stimulate thesynthesis and production of numerous extracellular matrix moleculesinvolved in tissue fibrosis. TGF-β stimulates connective tissue growthfactor (CTGF) synthesis in fibroblasts, vascular smooth muscle cells andendothelial cells. CTGF maintains a continuous and prolonged cycle ofexcessive scarring and fibrosis; thus TGF-β and CTGF may reflectactivity of the fibrotic process (Castro 2008). The central role ofTGF-β in inducing endothelial damage and fibroblast activation has ledinvestigators to target this molecule as a promising site for futuretherapies.

To date, no therapy has been shown to modify the overall diseaseprogression of SSc; therefore the development of a potentialdisease-modifying therapy in patients with SSc would address asignificant unmet medical need.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide new methods ofpreventing and/or treating systemic sclerosis in mammals, e.g., humans.

It is an object of the present invention to provide a composition andmethod for reducing the effects of systemic sclerosis in mammals, e.g.,humans.

It is an object of the present invention to modify the progression ofmyocardial fibrosis in patients with dcSSc, lcSSc, and/or SSc-PAH (e.g.,as compared to placebo and, e.g., as determined by cardiac magneticresonance imaging (MRI)).

It is an object of the present invention to improve right ventricularfunction in patients with dcSSc, lcSSc, and/or SSc-PAH (e.g., ascompared to placebo and, e.g., as determined by echocardiography) viatreatment with a thromboxane A₂ receptor antagonist (e.g., ifetroban).

It is an object of the present invention to reduce skin and peripheralvascular disease in patients with dcSSc, lcSSc, and/or SSc-PAH (e.g., ascompared to placebo and, e.g., as measured by digital ulcer imaging,active digital-tip ulcer count, patient reported outcome (VAS) and themodified Rodnan skin thickness score) via treatment with a thromboxaneA₂ receptor antagonist (e.g., ifetroban).

It is an object of the present invention to improve pulmonary functionin patients with dcSSc, lcSSc, and/or SSc-PAH (e.g., as compared toplacebo and, e.g., as measured by spirometry and diffusion capacity forcarbon monoxide (DL_(CO))) via treatment with a thromboxane A₂ receptorantagonist (e.g., ifetroban).

It is an object of the present invention to reduce laboratory andphysical evidence of inflammation in patients with dcSSc, lcSSc, and/orSSc-PAH (e.g., as compared to placebo as measured by serum biomarkers,erythrocyte sedimentation rate and physical examination).

It is an object of the present invention to improve quality of life inpatients with dcSSc, lcSSc, and/or SSc-PAH (e.g., compared to placeboand, e.g., as measured by the patient completed Quality of Life andScleroderma Health Assessment Questionnaires).

In accordance with the above objects, the present invention providescompositions and methods for preventing, reversing, ameliorating ortreating systemic sclerosis by administering a therapeutically effectiveamount of a thromboxane A₂ receptor antagonist (e.g., ifetroban or apharmaceutically acceptable salt thereof (e.g., ifetroban sodium)) to apatient in need thereof.

In accordance with the above objects, the present invention provides formethods of preventing, reversing, ameliorating or treating systemicsclerosis by administering a therapeutically effective amount of athromboxane A₂ receptor antagonist (e.g., ifetroban) to a patient inneed thereof.

In certain preferred embodiments, the mammal is a human patient withdcSSc, lcSSc, and/or SSc-PAH and the therapeutically effective amount ofthe thromboxane A₂ receptor antagonist or a pharmaceutically acceptablesalt thereof has an action selected from the group consisting of slowingthe progression of systemic sclerosis in the human patient as determinedby cardiac magnetic resonance imaging (MRI); improving the exercisecapacity in the human patient as determined by the six-minute walk test(6MWT); modifying the progression of myocardial fibrosis in the patientas determined by cardiac magnetic resonance imaging (MRI); improvingright ventricular function in the patient as determined byechocardiography; reducing skin and peripheral vascular disease in thepatient compared to placebo as measured by a test selected from thegroup consisting of digital ulcer imaging, active digital-tip ulcercount, patient reported outcome (VAS), the modified Rodnan skinthickness score, and any combination thereof; improving quality of lifein the patient with dcSSc, lcSSc, and/or SSc-PAH compared to placebo asmeasured by the patient completed Quality of Life and Scleroderma HealthAssessment Questionnaires; improving pulmonary function in the patientas measured by spirometry and diffusion capacity for carbon monoxide(DL_(CO)); improving laboratory and physical evidence of inflammation inthe compared to placebo as measured by serum biomarkers, erythrocytesedimentation rate, physical examination, or any combination thereof;and combinations of any of the foregoing.

In certain embodiments, the present invention is directed to a method oftreating and/or ameliorating systemic sclerosis, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a thromboxane A₂ receptor antagonist to provide a desiredplasma concentration of the thromboxane A₂ receptor antagonist (and/orits active metabolites) of about 0.1 ng/ml to about 100,000 ng/ml. Incertain embodiments, the therapeutically effective amount of athromboxane A2 receptor antagonist to provide a desired plasmaconcentration of the thromboxane A2 receptor antagonist of about 0.1ng/ml to about 10,000 ng/ml. In some embodiments, the afore-mentionedplasma concentration is a plasma concentration at steady state. In someembodiments, the afore-mentioned plasma concentration is a maximumplasma concentration (Cmax). In certain preferred embodiments, thethromboxane A2 receptor antagonist is ifetroban or a pharmaceuticallyacceptable salt thereof, e.g., ifetroban sodium.

In certain embodiments, the thromboxane A₂ receptor antagonist comprisesa therapeutically effective amount of[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (Ifetroban), and pharmaceutically acceptable salts thereof.

The invention is further directed to a method of treating dcScc(systemic sclerosis) or lcSSc (limited scleroderma) in a mammal in needof treatment thereof, comprising administering a therapeuticallyeffective amount of[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (ifetroban), or a pharmaceutically acceptable salt thereof to themammal. In certain embodiments, the thromboxane A₂ receptor antagonistcomprises a therapeutically effective amount of[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt (Ifetroban Sodium). In certain preferredembodiments, the mammal is a human patient. In certain preferredembodiments, the therapeutically effective amount of ifetroban slows theprogression of systemic sclerosis in the human patient and/or improvesthe exercise capacity in the human patient and/or improves pulmonaryfunction and/or quality of life in human patients suffering fromsystemic sclerosis. Certain embodiments of the invention are directed tothe method, wherein lcSSc patients are treated with a therapeuticallyeffective amount of ifetroban or a pharmaceutically acceptable saltthereof to prevent PAH from starting or progressing, or slowing itsprogression.

In any of the methods described above and others described herein, theifetroban is preferably administered in an amount effective to provide aplasma concentration of the ifetroban (and/or active metabolites ofifetroban) of about 1 ng/ml to about 100,000 ng/ml or of about 1 ng/mlto about 10,000 ng/ml for ifetroban itself, and in some embodiments fromabout 1 ng/ml to about 1,000 ng/ml. In some embodiments, theafore-mentioned plasma concentration is a plasma concentration at steadystate. In some embodiments, the afore-mentioned plasma concentration isa maximum plasma concentration (Cmax). In certain preferred embodimentswhere the mammal is a human patient, the therapeutically effectiveamount is from about 100 mg to about 2000 mg per day, or from about 10mg or about 100 mg to about 1000 mg per day, and certain embodimentsmore preferably from about 50 to about 500 mg per day, or from about 100mg to about 500 mg per day. The daily dose may be administered individed doses or in one bolus or unit dose or in multiple dosagesadministered concurrently. In this regard, the ifetroban may beadministered orally, intranasally, rectally, vaginally, sublingually,buccally, parenterally, or transdermally.

In certain preferred embodiments, the pharmaceutical compositiondescribed above, the therapeutically effective amount is from about 10mg to about 1000 mg ifetroban (or pharmaceutically acceptable saltthereof) per day. In certain preferred embodiments, the therapeuticallyeffective amount is from about 100 to about 500 mg per day, and incertain embodiments from about 150 mg to about 350 mg per day.

The present invention also relates to methods and compositions fortreating systemic sclerosis in a subject(s) or patient(s) in need oftreatment thereof, particularly, systemic sclerosis, the methodcomprising administering a therapeutically effective amount of athromboxane A₂ receptor antagonist to a subject(s) or patient(s) in needthereof. In particular, it relates to a method of treating or preventinga disorder that results in systemic sclerosis, in a subject(s) orpatient(s) in need of such treatment, comprising administering acomposition comprising administering a therapeutically effective amountof a thromboxane A₂ receptor antagonist to a patient in need thereof inan amount effective to reduce the rate of systemic sclerosis. Furtherprovided is a method of preventing systemic sclerosis in a subject(s) orpatient(s) in need of such treatment, comprising administering acomposition comprising a thromboxane A₂ receptor antagonist in an amounteffective to reduce the formation of sclerotic tissue that would occurin the absence of such treatment.

The invention is further directed to a pharmaceutical compositioncomprising a thromboxane A₂ receptor antagonist or a pharmaceuticallyacceptable salt thereof, the thromboxane A₂ receptor antagonist being inan amount effective to treat a human patient with dcSSc, lcSSc, and/orSSc-PAH. In certain preferred embodiments, the thromboxane A₂ receptorantagonist is ifetroban or a pharmaceutically acceptable salt thereof.In certain preferred embodiments, the ifetroban salt is ifetrobansodium. In certain preferred embodiments, the therapeutically effectiveamount is from about 10 mg to about 1000 mg per day, and in certainembodiments from about 150 mg to about 350 mg. In certain preferredembodiments, the pharmaceutical composition is an oral solid dosageform.

The phrase “therapeutically effective amount” refers to that amount of asubstance that produces some desired local or systemic effect at areasonable benefit/risk ratio applicable to any treatment. The effectiveamount of such substance will vary depending upon the subject anddisease condition being treated, the weight and age of the subject, theseverity of the disease condition, the manner of administration and thelike, which can readily be determined by one of ordinary skill in theart.

The term “thromboxane A2 receptor antagonist” as used herein refers to acompound that inhibits the expression or activity of a thromboxanereceptor by at least or at least about 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% in astandard bioassay or in vivo or when used in a therapeutically effectivedose. In certain embodiments, a thromboxane A2 receptor antagonistinhibits binding of thromboxane A₂ to the receptor. Thromboxane A2receptor antagonists include competitive antagonists (i.e., antagoniststhat compete with an agonist for the receptor) and non-competitiveantagonists. Thromboxane A2 receptor antagonists include antibodies tothe receptor. The antibodies may be monoclonal. They may be human orhumanized antibodies. Thromboxane A2 receptor antagonists also includethromboxane synthase inhibitors, as well as compounds that have boththromboxane A2 receptor antagonist activity and thromboxane synthaseinhibitor activity.

As used herein, the term “unit dose” refers to physically discrete unitssuitable as unitary dosages for mammalian subjects, each unit containingas the active ingredient a predetermined quantity of the thromboxane A2receptor antagonist.

The term “comprising” is an inclusive term interpreted to meancontaining, embracing, covering or including the elements listedfollowing the term, but not excluding other unrecited elements.

A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

As used herein, the term “treating” or “treatment” of a disease includespreventing the disease from occurring in an animal that may bepredisposed to the disease but does not yet experience or exhibitsymptoms of the disease (prophylactic treatment), inhibiting the disease(slowing or arresting its development), providing relief from thesymptoms or side-effects of the disease (including palliativetreatment), and relieving the disease (causing regression of thedisease).

The term “parenteral” as used herein, includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the above stated objects, it is believed thatadministration of a therapeutically effective amount of a thromboxane A₂receptor antagonist to a subject(s) or patient(s) in need thereof canprevent and/or treat systemic sclerosis.

Thromboxane A₂ Receptor Antagonist

The discovery and development of thromboxane A₂ receptor antagonists hasbeen an objective of many pharmaceutical companies for approximately 30years (see, Dogne J-M, et al., Exp. Opin. Ther. Patents 11: 1663-1675(2001)). Certain individual compounds identified by these companies,either with or without concomitant thromboxane A₂ synthase inhibitoryactivity, include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI),UK-147535 (Pfizer), GR 32191 (Glaxo), and S-18886 (Servier). Preclinicalpharmacology has established that this class of compounds has effectiveantithrombotic activity obtained by inhibition of the thromboxanepathway. These compounds also prevent vasoconstriction induced bythromboxane A₂ and other prostanoids that act on the thromboxane A₂receptor within the vascular bed, and thus may be beneficial for use inpreventing and/or treating hepatorenal syndrome and/or hepaticencephalopathy.

Suitable thromboxane A2 receptor antagonists for use in the presentinvention may include, for example, but are not limited to smallmolecules such as ifetroban (BMS;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylamino)carbony-1]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2yl]methyl]benzenepropanoic acid), as well as others described in U.S.Patent Application Publication No. 2009/0012115, the disclosure of whichis hereby incorporated by reference in its entirety.

Additional thromboxane A2 receptor antagonists suitable for use hereinare also described in U.S. Pat. No. 4,839,384 (Ogletree); U.S. Pat. No.5,066,480 (Ogletree, et al.); U.S. Pat. No. 5,100,889 (Misra, et al.);U.S. Pat. No. 5,312,818 (Rubin, et al.); U.S. Pat. No. 5,399,725 (Poss,et al.); and U.S. Pat. No. 6,509,348 (Ogletree), the disclosures ofwhich are hereby incorporated by reference in their entireties. Thesemay include, but are not limited to, interphenylene 7-oxabicyclo-heptylsubstituted heterocyclic amide prostaglandin analogs as disclosed inU.S. Pat. No. 5,100,889, including:

-   [1S-(1α, 2α, 3α,    4α)]-2-[[3-[4-[[(4-cyclo-hexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoic    acid (SQ 33,961), or esters or salts thereof;-   [1S-(1α, 2α, 3α,    4α)]-2-[[3-[4-[[[(4-chloro-phenyl)-butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic    acid or esters, or salts thereof;-   [1S-(1α, 2α, 3α,    4α)]-3-[[3-[4-[[(4-cycloh-exylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1]hept-2-yl]benzene    acetic acid, or esters or salts thereof;-   [1S-(1α, 2α, 3α,    4α)]-[2-[[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]acetic    acid, or esters or salts thereof;-   [1S-(1α, 2α, 3α,    4α]-2-[[3-[4-[[(7,7-dime-thyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoic    acid, or esters or salts thereof.-   7-oxabicycloheptyl substituted heterocyclic amide prostaglandin    analogs as disclosed in U.S. Pat. No. 5,100,889, issued Mar. 31,    1992, including [1S-[1α, 2α (Z), 3α,    4α)]-6-[3-[4-[[(4-cyclohexylbutyl)amino]-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[(1-pyrrolidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[(cyclohexylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoic    acid or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(2-cyclohexyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[[2-(4-chloro-phenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]-6-[3-[4-[[(4-chlorophenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[[4-(4-chloro-phenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4.alpha.-[[-(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters, or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α]]-6-[3-[4-[(propylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-butylphenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo[2-.2.1]hept-2-yl]-4-hexenamide;-   [1S-[1α, 2α (Z), 3α,    4α)]]-7-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo    (2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts thereof;-   [1S-[1α, 2α (Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic    acid or esters or salts thereof;-   [1S-[1α, 2α, 3α, 4α)]-6-[3-[4-[[(7,    7-dimethyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;-   [1S-[1α, 2α(E), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid;-   [1S-[1α, 2α, 3α,    4α)]-3-[4-[[(4-(cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoic    acid or esters or salts thereof,-   [1S-[1α, 2α(Z), 3α,    4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoic    acid, or esters or salts thereof;

7-oxabicycloheptane and 7-oxabicycloheptene compounds disclosed in U.S.Pat. No. 4,537,981 to Snitman et al, the disclosure of which is herebyincorporated by reference in its entirety, such as [1S-(1α, 2α(Z),3α(1E, 3S*, 4R*),4α)]]-7-[3-(3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid (SQ 29,548); the 7-oxabicycloheptane substituted aminoprostaglandinanalogs disclosed in U.S. Pat. No. 4,416,896 to Nakane et al, thedisclosure of which is hereby incorporated by reference in its entirety,such as [1S-[1α, 2α(Z), 3α,4α)]]-7-[3-[[2-(phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid; the 7-oxabicycloheptane substituted diamide prostaglandin analogsdisclosed in U.S. Pat. No. 4,663,336 to Nakane et al, the disclosure ofwhich is hereby incorporated by reference in its entirety, such as,[1S-[1α, 2α(Z), 3α,4α)]]-7-[3-[[[[(1-oxoheptyl)amino]-acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid and the corresponding tetrazole, and [1S-[1α, 2α(Z),3α,4α)]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acetyl]amino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoicacid;

7-oxabicycloheptane imidazole prostaglandin analogs as disclosed in U.S.Pat. No. 4,977,174, the disclosure of which is hereby incorporated byreference in its entirety, such as [1S-[1α, 2α(Z), 3α,4α)]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-1H-imidazole-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid or its methyl ester;

-   [1S-[1α, 2α(Z), 3α,    4α)]]-6-[3-[[4-(3-cyclohexyl-propyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid or its methyl ester;-   [1S-[1α, 2α(X(Z), 3α,    4α)]]-6-[3-[[4-(4-cyclohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid or its methyl ester;-   [1S-[1α, 2α(Z), 3α,    4α]]-6-[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic    acid or its methyl ester; or-   [1S-[1α, 2α(Z), 3α,    4α)]]-6-[3-[[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo-[2.2.1]-hept-2-yl]-4-hexenoic    acid, or its methyl ester;

The phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No. 4,258,058to Witte et al, the disclosure of which is hereby incorporated byreference in its entirety, including4-[2-(benzenesulfamido)ethyl]phenoxy-acetic acid (BM 13,177-BoehringerMannheim), the sulphonamidophenyl carboxylic acids disclosed in U.S.Pat. No. 4,443,477 to Witte et al, the disclosure of which is herebyincorporated by reference in its entirety, including4-[2-(4-chlorobenzenesulfonamido)ethyl]-phenylacetic acid (BM 13,505,Boehringer Mannheim), the arylthioalkylphenyl carboxylic acids disclosedin U.S. Pat. No. 4,752,616, the disclosure of which is herebyincorporated by reference in its entirety, including4-(3-((4-chlorophenyl) sulfonyl)propyl)benzene acetic acid.

Other examples of thromboxane A₂ receptor antagonists suitable for useherein include, but are not limited to vapiprost (which is a preferredexample),(E)-5-[[[(pyridinyl)]3-(trifluoromethyl)phenyl]methylene]amino]-oxy]pentanoicacid also referred to as R68,070-Janssen Research Laboratories,3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,2-dimethylpropanoicacid [(L-655240 Merck-Frosst) Eur. J. Pharmacol. 135(2):193, March 17,87],5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenyl)-2-trifl-uoromethyl-1,3-dioxan-5-yl)heptenoicacid (ICI 185282, Brit. J. Pharmacol. 90 (Proc. Suppl):228 P-Abs, March87), 5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl]heptenoic acid(ICI 159995, Brit. J. Pharmacol. 86 (Proc. Suppl):808 P-Abs., December85),N,N′-bis[7-(3-chlorobenzeneamino-sulfony-1)-1,2,3,4-tetrahydro-isoquinolyl]disulfonylimide(SKF 88046, Pharmacologist 25(3):116 Abs., 117 Abs, August 83),(1.alpha.(Z)-2.beta.,5.alpha.]-(+)-7-[5-[[(1,1′-biphenyl)-4-yl]-methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoicacid (AH 23848-Glaxo, Circulation 72(6):1208, December 85, levallorphanallyl bromide (CM 32,191 Sanofi, Life Sci. 31 (20-21):2261, November 15,82),(Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo[2.2.1]heptyl-5-hepta-3Z-enoicacid, 4-phenyl-thiosemicarbazone (EP092-Univ. Edinburgh, Brit. J.Pharmacol. 84(3):595, March 85); GR 32,191 (Vapiprost)-[1R-[1.alpha.(Z),2.beta., 3.beta.,5.alpha.]]-(+)-7-[5-([1,1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoicacid; ICI192,605-4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hexenoicacid; BAY u 3405(ramatroban)-3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-c-arbazole-9-propanoicacid; or ONO 3708-7-[2.alpha.,4.alpha.-(dimethylmethano)-6.beta.-(2-cyclopentyl-2.beta.-hydroxyacetami-do)-1.alpha.-cyclohexyl]-5(Z)-heptenoicacid;(.+−.)(5Z)-7-[3-endo-((phenylsulfonyl)amino]-bicyclo[2.2.1]hept-2-exo-yl]-heptenoicacid (S-1452, Shionogi domitroban, Anboxan®.);(−)6,8-difluoro-9-p-methylsulfonylben-zyl-1,2,3,4-tetrahydrocarbazol-1-yl-aceticacid (L670596, Merck) and(3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoicacid (L655240, Merck).

The preferred thromboxane A2 receptor antagonist of the presentinvention is ifetroban or any pharmaceutically acceptable salts thereof.

In certain preferred embodiments the preferred thromboxane A2 receptorantagonist is ifetroban sodium (known chemically as[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt.

Two known pharmacological actions of ifetroban resulting from TPantagonism include inhibition of smooth muscle contractions (Ogletree,1992) and inhibition of platelet shape change and aggregation. Thesedivergent pharmacological actions suggest varied potential therapeuticindications. Recently, the effect of TP receptor antagonism was studiedin mice with mechanical constriction of the pulmonary artery, a model ofPAH-associated right ventricular hypertrophy. Treatment with ifetrobanreduced right ventricular fibrosis and cardiomyocyte hypertrophy inpulmonary artery banded mice, and increased ratio of the early (E) tolate (A) ventricular filling velocities (E/A ratio), one indicator ofcardiac efficiency. This was associated with augmented right ventricularexpression of anti-fibrotic and muscularization genes, as well asdecreased expression of genes associated with inflammation.

Systemic sclerosis (SSc, scleroderma) is potential therapeutic target ofifetroban given the known role of platelet activation in the initiationand perpetuation of autoimmune inflammatory processes and thereforefibrosis. By antagonizing the TP receptor, ifetroban is capable ofinhibiting signals from thromboxane and F2-isoprostane not only onplatelets but also on endothelium and other immune cells potentiallystemming from the inflammation.

Given the preclinical work indicating that administration of ifetrobanis capable of preventing cardiac fibrosis in a model of pulmonaryarterial hypertension, evaluating a treatment that may delay or inhibittissue fibrosis could provide significant improvement in quality of lifefor these patients. In addition, ifetroban could potentially also modifythe skin disease in SSc and skin assessments will be included for allpatients in this study.

The heart is a major organ involved in scleroderma and the presence ofcardiac involvement in SSc is often underestimated and is a sign of poorprognosis (Champion). SSc patients, especially those with PAH, oftenexperience a poor quality of life; many with severe disease are oftenunable to perform even simple routine standard of care daily activitieswithout severe shortness of breath, fatigue and fainting, and becausethey experience a risk of early death due to the rapid deterioration oftheir pulmonary and cardiac systems, the need for effective treatment isimportant. This study will provide safety and initial efficacy data forifetroban in patients with dcSSc, lcSSc, and SSc-PAH.

Methods of Treatment

In certain embodiments of the present invention there is provided amethod of preventing and/or treating and/or ameliorating systemicsclerosis in one or more organs or tissues in a patient or patientpopulation by administration of a therapeutically effective amount of athromboxane A₂ receptor antagonist to a patient(s) in need thereof.

The administration of a therapeutically effective amount of athromboxane A₂ receptor antagonist may be accomplished via anytherapeutically useful route of administration, including but notlimited to orally, intranasally, rectally, vaginally, sublingually,buccally, parenterally, or transdermally. In certain preferredembodiments, the thromboxane A₂ receptor antagonist is administeredparenterally. In certain further embodiments, the thromboxane A₂receptor antagonist is administered by intra-articular injection. Incertain further embodiments, the thromboxane A₂ receptor antagonist isadministered directly to the affected anatomic site. In anotherembodiment, the thromboxane A₂ receptor antagonist is administeredthrough the hepatic artery.

In any of the methods described above and others described herein, thethromboxane A₂ receptor antagonist (e.g., ifetroban) is preferablyadministered in an amount effective to provide a plasma concentration ofthe thromboxane A₂ receptor antagonist (and/or active metabolitesthereof) of about 1 ng/ml to about 100,000 ng/ml or of about about 0.1ng/ml; or 1 ng/ml to about 10,000 ng/ml for ifetroban itself, and insome embodiments from about 1 ng/ml to about 1,000 ng/ml or more (e.g.,in some embodiments up to about 10,000 ng/ml, and in further embodimentsup to about 100,000 ng/ml). In some embodiments, the afore-mentionedplasma concentration is a plasma concentration at steady state. In someembodiments, the afore-mentioned plasma concentration is a maximumplasma concentration (Cmax). In certain preferred embodiments where themammal is a human patient, the therapeutically effective amount is fromabout 100 mg to about 2000 mg per day, or from about 10 mg or about 100mg to about 1000 mg per day, and certain embodiments more preferablyfrom about 100 to about 500 mg per day. The daily dose may beadministered in divided doses or in one bolus or unit dose or inmultiple dosages administered concurrently. In this regard, theifetroban may be administered orally, intranasally, rectally, vaginally,sublingually, buccally, parenterally, or transdermally.

In one embodiment where the mammal is a human patient, thetherapeutically effect amount of ifetroban is about 250 mg daily, takenorally.

The dose administered should be adjusted according to age, weight andcondition of the patient, as well as the route of administration, dosageform and regimen and the desired result.

In order to obtain the desired plasma concentration of thromboxane A₂receptor antagonists for the treatment or prevention of systemicsclerosis, daily doses of the thromboxane A₂ receptor antagonistspreferably range from about 0.1 mg to about 5000 mg. In certainpreferred embodiments, the daily dose of thromboxane A₂ receptorantagonists for the treatment or prevention of systemic sclerosis mayrange from about 1 mg to about 2000 mg; about 10 mg to about 1000 mg;from about 100 mg to about 1000 mg; from about 50 mg to about 500 mg;about 100 mg to about 500 mg; or from about 150 mg to about 300 mg perday.

In certain preferred embodiments, a daily dose of ifetroban sodium fromabout 10 mg to about 500 mg, preferably from about 150 mg to about 300mg (ifetroban free acid amounts) will produce therapeutically effectiveplasma levels of ifetroban free acid for the treatment or prevention ofsystemic sclerosis.

When the thromboxane A₂ receptor antagonist is ifetroban, the desiredplasma concentration for providing an inhibitory effect ofA₂/prostaglandin endoperoxide receptor (TP) activation, and thus areduction of cerebral microvascular activation should be greater thanabout 10 ng/mL (ifetroban free acid). Some inhibitory effects ofthromboxane A₂ receptor antagonist, e.g., ifetroban, may be seen atconcentrations of greater than about 1 ng/mL.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

In certain preferred embodiments where the thromboxane A₂ receptorantagonist is ifetroban or a pharmaceutically acceptable salt thereof, adaily dose of ifetroban sodium from about 10 mg to about 500 mg,preferably from about 150 mg to about 300 mg (ifetroban free acidamounts) will produce effective plasma levels of ifetroban free acid.

Pharmaceutical Compositions

The thromboxane A₂ receptor antagonists of the present invention may beadministered by any pharmaceutically effective route. For example, thethromboxane A₂ receptor antagonists may be formulated in a manner suchthat they can be administered orally, intranasally, rectally, vaginally,sublingually, buccally, parenterally, or transdermally, and, thus, beformulated accordingly.

In certain embodiments, the thromboxane A₂ receptor antagonists may beformulated in a pharmaceutically acceptable oral dosage form. Oraldosage forms may include, but are not limited to, oral solid dosageforms and oral liquid dosage forms.

Oral solid dosage forms may include, but are not limited to, tablets,capsules, caplets, powders, pellets, multiparticulates, beads, spheresand any combinations thereof. These oral solid dosage forms may beformulated as immediate release, controlled release, sustained(extended) release or modified release formulations.

The oral solid dosage forms of the present invention may also containpharmaceutically acceptable excipients such as fillers, diluents,lubricants, surfactants, glidants, binders, dispersing agents,suspending agents, disintegrants, viscosity-increasing agents,film-forming agents, granulation aid, flavoring agents, sweetener,coating agents, solubilizing agents, and combinations thereof.

Depending on the desired release profile, the oral solid dosage forms ofthe present invention may contain a suitable amount ofcontrolled-release agents, extended-release agents, modified-releaseagents.

Oral liquid dosage forms include, but are not limited to, solutions,emulsions, suspensions, and syrups. These oral liquid dosage forms maybe formulated with any pharmaceutically acceptable excipient known tothose of skill in the art for the preparation of liquid dosage forms.For example, water, glycerin, simple syrup, alcohol and combinationsthereof.

In certain embodiments of the present invention, the thromboxane A2receptor antagonists may be formulated into a dosage form suitable forparenteral use. For example, the dosage form may be a lyophilizedpowder, a solution, suspension (e.g., depot suspension).

In other embodiments, the thromboxane A2 receptor antagonists may beformulated into a topical dosage form such as, but not limited to, apatch, a gel, a paste, a cream, an emulsion, liniment, balm, lotion, andointment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples are not meant to be limiting and representcertain embodiments of the present invention.

Example 1

In this example, ifetroban sodium capsules are prepared with thefollowing ingredients listed in Table 1:

TABLE 1 Ingredients Percent by weight Na salt of Ifetroban 35 Mannitol50 Microcrystalline Cellulose 8 Crospovidone 3.0 Magnesium Oxide 2.0Magnesium Stearate 1.5 Colloidal Silica 0.3

The sodium salt of ifetroban, magnesium oxide, mannitol,microcrystalline cellulose, and crospovidone is mixed together for about2 to about 10 minutes employing a suitable mixer. The resulting mixtureis passed through a #12 to #40 mesh size screen. Thereafter, magnesiumstearate and colloidal silica are added and mixing is continued forabout 1 to about 3 minutes.

The resulting homogeneous mixture is then filled into capsules eachcontaining 50 mg, ifetroban sodium salt.

Example II

In this example, 1000 tablets each containing 400 mg of Ifetroban sodiumare produced from the following ingredients listed in Table 2:

TABLE 2 Ingredients Amount Na salt of Ifetroban 400 gm Corn Starch 50 gGelatin 7.5 g Microcrystalline Cellulose (Avicel) 25 g MagnesiumStearate 2.5 g

Example III

In this example. An injectable solution of ifetroban sodium is preparedfor intravenous use with the following ingredients listed in Tables 3aand 3b:

TABLE 3a Ingredients Amount Ifetroban Sodium 2500 mg Methyl Paraben 5 mgPropyl Paraben 1 mg Sodium Chloride 25,000 mg Water for injection q.s. 5liter

TABLE 3b Ingredients Amount Ifetroban Sodium 52.5 mg Sodium PhosphateDibasic Anhydrous 345 mg Sodium Phosphate Monobasic Anhydrous 1.0 gSodium Chloride 21.5 g Water for injection q.s. 5 liter

The sodium salt of ifetroban, buffers and sodium chloride are dissolvedin 3 liters of water for injection and then the volume is brought up to5 liters. The solution is filtered through a sterile filter andaseptically filled into pre-sterilized vials which are then closed withpre-sterilized rubber closures. Each vial contains a concentration of 50mg of active ingredient per 5 ml of solution.

Example IV

In Example 4, a phase 2 multicenter, randomized, double-blind,placebo-controlled, study in patients with dcSSc, lcSSc or SSc-PAH.There will be a 365 day blinded treatment in this study and withassessments being performed at Screening (−14 days to Study Hour 0),Baseline (Study Visit 1/Study Hour 0), Week 12 (Study Visit 2), Week 26(Study Visit 3), Week 39 (Study Visit 4), Week 52 (Study Visit 5), andWeek 56 (Study Visit 6) is conducted. Safety will be monitoredthroughout the Treatment Period. Separate randomization schemes will begenerated for the SSc-PAH and dcSSc patient groups allowing enrollmentto progress independently between patient groups. Fourteen (14) patientswith SSc-PAH will be enrolled in this study, with 10 receiving ifetrobanand 4 receiving matching placebo. These patients may have lcSSc ordcSSc. Twenty (20) patients with dcSSc will be enrolled in this study,with 14 receiving ifetroban and 6 receiving matching placebo. Inclusioncriteria for SSc are: Adults with SSc according to the 2013 ACR/EULARcriteria (Appendix A) and with diffuse cutaneous involvement within 5years following initial diagnosis as defined by the onset of the firstnon-Raynaud symptom. Inclusion criteria for SSc-PAH are: Adults withconfirmed SSc-PAH (limited or diffuse SSc); stable oral therapy for PAHfor at least 30 days; and New York Heart Association Class I-III HeartFailure.

Subjects randomized to oral ifetroban will be administered five 50 mgcapsules by mouth per day (250 mg daily dose) for 365 days. Subjectrandomized to placebo will take five matching placebo capsules by mouthper day for 365 days.

The drug product is supplied as a capsule dosage form (size #1, whiteopaque) for oral administration. The formulation consists of ifetroban,mannitol, microcrystalline cellulose, crospovidone, magnesium oxide,colloidal silicon dioxide, and magnesium stearate. Capsules are filledinto high density polyethylene bottles and sealed with screw-capclosures. Placebo for Ifetroban capsules are formulated as a dry powderblend filled into capsules. The formulation consists of microcrystallinecellulose, crospovidone, colloidal silicon dioxide, and magnesiumstearate. Capsules are filled into high density polyethylene bottles andsealed with screw-cap closures. Ifetroban and placebo capsules should beadministered in a fasting state. Meals following administration shouldbe held for at least 30 minutes following study drug administration.

The objectives of the study are as follows:

-   -   To determine the safety of ifetroban in patients with diffuse        cutaneous SSc or SSc-PAH compared to placebo as measured by        treatment emergent adverse events (TEAE) and standard laboratory        assessments.    -   To determine if ifetroban can modify the progression of        myocardial fibrosis in patients with diffuse SSc or SSc-PAH        compared to placebo as determined by cardiac magnetic resonance        imaging (MRI).    -   To determine if ifetroban improves right ventricular function in        patients with diffuse cutaneous SSc or SSc-PAH compared to        placebo as determined by echocardiography.    -   To determine if ifetroban improves exercise capacity in patients        with diffuse cutaneous SSc or SSc-PAH compared to placebo as        determined by the six-minute walk test (6MWT).    -   To determine if ifetroban reduces skin and peripheral vascular        disease in patients with diffuse cutaneous SSc or SSc-PAH        compared to placebo as measured by digital ulcer imaging, active        digital-tip ulcer count, patient reported outcome (VAS) and the        modified Rodnan skin thickness score.    -   To determine if ifetroban improves quality of life in patients        with diffuse cutaneous SSc or SSc-PAH compared to placebo as        measured by the patient completed Quality of Life and        Scleroderma Health Assessment Questionnaires.    -   To determine if ifetroban improves pulmonary function in        patients with diffuse cutaneous SSc or SSc-PAH compared to        placebo as measured by spirometry and diffusion capacity for        carbon monoxide (DLCO).    -   To determine if ifetroban improves laboratory and physical        evidence of inflammation in patients with diffuse cutaneous SSc        or SSc-PAH compared to placebo as measured by serum biomarkers,        erythrocyte sedimentation rate and physical examination.    -   To determine if ifetroban alters biomarkers in the skin in        patients with diffuse cutaneous SSc compared to placebo as        measured by skin biopsy biomarkers.

CONCLUSION

In the preceding specification, the invention has been described withreference to specific exemplary embodiments and examples thereof. Itwill, however, be evident that various modifications and changes may bemade thereto without departing from the broader spirit and scope of theinvention as set forth in the claims that follow. The specification isto be regarded in an illustrative manner rather than a restrictivesense.

REFERENCES

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1-19. (canceled)
 20. A method of reducing presence of digital ulcers ina patient with diffuse systemic sclerosis, comprising administering 250mg per day of[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (ifetroban), or a pharmaceutically acceptable salt thereof, to thepatient, thereby reducing presence of digital ulcers.
 21. The method ofclaim 20, wherein the presence of digital ulcers is measured in thepatient by digital ulcer imaging.
 22. The method of claim 20, whereinthe presence of digital ulcers is measured in the patient by activedigital-tip ulcer count.
 23. The method of claim 20, wherein the[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (ifetroban), or a pharmaceutically acceptable salt thereof, isadministered to the patient intravenously.
 24. The method of claim 20,wherein the[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (ifetroban), or a pharmaceutically acceptable salt thereof, isadministered to the patient orally.
 25. The method of claim 20, whereinthe[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (ifetroban), or a pharmaceutically acceptable salt thereof, is1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid monosodium salt (Ifetroban Sodium).
 26. The method of claim 25,wherein the Ifetroban Sodium is administered to the patient orally. 27.The method of claim 25, wherein the Ifetroban Sodium is administered tothe patient intravenously.